title: The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin.
abstract: Ischemia causes AKI as a result of ATP depletion, and rapid recovery of ATP on reperfusion is important to minimize tissue damage. ATP recovery is often delayed, however, because ischemia destroys the mitochondrial cristae membranes required for mitochondrial ATP synthesis. The mitochondria-targeted compound SS-31 accelerates ATP recovery after ischemia and reduces AKI, but its mechanism of action remains unclear. Here, we used a polarity-sensitive fluorescent analog of SS-31 to demonstrate that SS-31 binds with high affinity to cardiolipin, an anionic phospholipid expressed on the inner mitochondrial membrane that is required for cristae formation. In addition, the SS-31/cardiolipin complex inhibited cytochrome c peroxidase activity, which catalyzes cardiolipin peroxidation and results in mitochondrial damage during ischemia, by protecting its heme iron. Pretreatment of rats with SS-31 protected cristae membranes during renal ischemia and prevented mitochondrial swelling. Prompt recovery of ATP on reperfusion led to rapid repair of ATP-dependent processes, such as restoration of the actin cytoskeleton and cell polarity. Rapid recovery of ATP also inhibited apoptosis, protected tubular barrier function, and mitigated renal dysfunction. In conclusion, SS-31, which is currently in clinical trials for ischemia-reperfusion injury, protects mitochondrial cristae by interacting with cardiolipin on the inner mitochondrial membrane.
authors.affiliation: Departments of Pharmacology, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Birk
authors.forename: Shaoyi
authors.initials: S
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: Soong
authors.forename: William
authors.initials: W
authors.lastname: Mills
authors.forename: Pradeep
authors.initials: P
authors.lastname: Singh
authors.forename: J David
authors.initials: JD
authors.lastname: Warren
authors.forename: Surya V
authors.initials: SV
authors.lastname: Seshan
authors.forename: Joel D
authors.initials: JD
authors.lastname: Pardee
authors.forename: Hazel H
authors.initials: HH
authors.lastname: Szeto
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002308:Cardiolipins / Q000378:metabolism*; D003578:Cytochrome-c Peroxidase / Q000378:metabolism*; D007511:Ischemia / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism
chemical_list: D002308:Cardiolipins; D009842:Oligopeptides; D017382:Reactive Oxygen Species; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide; D000255:Adenosine Triphosphate; D003578:Cytochrome-c Peroxidase; D002118:Calcium